The listing or discussion of a prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.
Because of its fundamental role in molecular biological processes, DNA represents an important target for drug action. Compounds that can recognise defined sequences of DNA have a wide variety of potential uses, such as the modulation of gene expression.
The outer surface of double-helical DNA has two channels, namely the major and minor grooves. Both of these grooves contain chemical information by way of arrangements of hydrogen-bond donors and acceptors, electrostatic charges, dipoles, hydrophobic regions and so on.
The major groove contains approximately twice the information content of the minor groove in terms of the number of potential hydrogen-bonding contacts. In view of this, the major groove is the preferred recognition site for cellular proteins such as control proteins, promoters and repressors.
In contrast, the minor groove is normally (with a few exceptions) relatively unoccupied. The vulnerability of the minor groove makes it a particularly useful target for compounds that bind to DNA. Indeed, perhaps for this very reason, the minor groove is the binding site for certain naturally occurring antibiotics (such as netropsin and distamycin).
Netropsin and distamycin are oligopeptides based on pyrrole amino acid monomers. These compounds both bind to DNA with dissociation constants in the order of 10−5 M. They also show a preference for AT-rich regions of DNA. Although they have intrinsic biological activity, netropsin and distamycin also have many limitations including toxicity, moderate affinity and limited selectivity. A number of workers have therefore prepared synthetic analogues of netropsin and distamycin, with a view to overcoming these disadvantages. Many of these compounds are reviewed by Sondhi et al (Curr. Med. Chem. 4, 313 (1997)), Reddy et al. (Pharmacology & Therapeutics 84, 1 (1999)), Wemmer (Biopolymers 52, 197 (2001)) and Dervan (Bioorg. Med. Chem. 9, 2215 (2001)).
Compounds designed to bind to DNA regions containing GC base pairs are described in, for example: Anti-Cancer Drug Design 5, 3 (1990); Proc. Natl. Acad. Sci. USA 89, 7586 (1992); Biochemistry 32, 4237 (1993); Science 266, 647 (1994); Anti-Cancer Drug Design 10, 155 (1995); Bioorg. Med. Chem. 8, 985 (2000); and Mol. Biol. 34, 357 (2000). Various other netropsin and distamycin analogues are described in: J. Am. Chem. Soc. 114(15), 5911 (1992); Biochemistry 31, 8349 (1992); Bioconjugate Chem. 5, 475 (1994); Biochem. Biophys. Res. Commun. 222, 764 (1996); J. Med. Chem. 43, 3257 (2000); and Tetrahedron 56, 5225 (2000). Further, the use of certain netropsin and distamycin analogues as antimicrobial, antiviral and/or antitumor agents is described in Molecular Pharmacology 54, 280 (1998), Bioorg. Med. Chem. Lett. 6(18), 2169 (1996), J. Med. Chem. 45, 805 (2002), Bioorg. Med. Chem. Lett. 12, 2007 (2002), international patent applications WO 97/28123, WO 98/21202, WO 01/74898 and WO 02/00650, as well as in U.S. Pat. Nos. 4,912,199, 5,273,991, 5,637,621, 5,698,674 and 5,753,629. Methods of synthesising analogues of netropsin and distamycin are described in U.S. Pat. No. 6,090,947.
Cellular uptake of distamycin analogues is described in Bioorg. Med. Chem. Lett. 11, 769 (2001).
Further compounds designed to bind to DNA are described in U.S. Pat. No. 6,143,901, which discloses oligomers of between 6 and 30 heterocyclic groups, in which the group linking the heterocycles may be methyleneamino, amido, thioamido, iminydyl or ethenylene. Amido (and its heteroanalogues) is described as the preferred linking group. There is no preference given in U.S. Pat. No. 6,143,901 in relation to the number or location of ethenylene linking groups, should such groups be present. Moreover, there is no suggestion that ethenylene-containing compounds may have any advantages over compounds containing other linkers (e.g. amido).
Analogues of distamycin are described in Tet. Lett. 37(43), 7801-7804 (1996), wherein an amide group linking two pyrroles of an oligopyrrole compound is replaced with either a diketo or alkenylene linker. The resulting compounds are described as having significantly lower binding affinity for DNA compared to the analogous amido-linked compounds.
Minor groove binding compounds comprising an acrylamide-type linker between the 2-position of a pyrrole group and a terminal basic group are described in J. Am. Chem. Soc. 122, 1602-1608 (2000), ibid. 123, 5158-5159 (2001), ibid. 125, 3471-3485 (2003), ibid. 126, 3406-3407 (2004), Chem. Eur. J. 8, 4781-4790 (2002), Chem. & Biol. 10, 751-758 (2003) and Bioconjugate Chem. 17, 715-720 (2006).
Further minor groove binding compounds comprising an acrylamide-type linker between the 3-position of a pyrrole group and a terminal aromatic group are described in J. Med. Chem. 47, 2133-2156 (2004).
None of the above-mentioned documents disclose or suggest compounds having affinity for DNA, which compounds comprise oligomers of cyclic groups in which an alkenylene moiety directly connects a cyclic group at the “amino” terminus to the adjacent cyclic group and at least one of the cyclic groups connected via the alkenylene moiety is other than a pyrrole (or 5-membered heterocycle).